Calcium formate for use as a dietary supplement

ABSTRACT

A calcium formate composition for oral administration to an individual for the purpose of supplementary dietary calcium is disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 10/636,157, filedAug. 7, 2003, now abandoned which is a continuation of U.S. Ser. No.10/326,789, filed Dec. 19, 2001, now abandoned which is a continuationof U.S. Ser. No. 09/961,729, filed Sep. 24, 2001, now U.S. Pat. No.6,528,542 which is a continuation-in-part of U.S. Ser. No. 09/469,513,filed Dec. 22, 1999 now U.S. Pat. No. 6,160,016 and Ser. No. 09/649,710,filed Aug. 25, 2000 now U.S. Pat. No. 6,489,361. These documents areincorporated by reference as if set forth fully herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT --BACKGROUND OF THE INVENTION

A. Calcium Formate as a Phosphate Binder

Phosphorus retention plays a major role in chronic renal failure in thedevelopment of both secondary hyperparathyroidism and osteodystrophy.Bricker, N., S. et al., Archives of Internal Medicine 123:543-553(1969); Rubini, M. E. et al., Archives of Internal Medicine 124:663-669(1969); Slatopolsky, E., et al., Journal of Clinical Investigation50:492-499 (1971); Bricker, N. S., New England Journal of Medicine286:1093-1099 (1972); Slatopolsky, E. S., et al., Kidney Int. 2:147-151(1972).

Antacids are often used to bind dietary phosphorus to prevent phosphorusretention and prevent its absorption. This process is referred to asphosphorus binding and appears to be a chemical reaction between dietaryphosphorus and the cation present in the binder compound, which isusually albumin or calcium. The binding results in the formation ofinsoluble and unabsorbable phosphate compounds, adsorption of phosphorusions on the surface of binder particles, or a combination of both.

Presently-used antacids are inefficient at binding phosphorus in vivo.For example, a recent study by Ramirez, et al., noted that even thoughaluminum-containing or calcium-containing antacids were administered inlarge excess, they bound only 19-35 percent of dietary phosphorus.Ramirez, J. A., et al., Kidney Int. 30:753-759 (1986). Similarconclusions can be derived from data presented in earlier studies.Kirsner, J. B., Journal of Clinical Investigation, 22:47-52 (1943);Clarkson, E. M., et al., Clinical Science 43:519-531 (1972); Cam, J. M.,et al., Clinical Science and Molecular Medicine 51:407-414 (1976); Man,N. K. et al., Proceedings of the European Dialysis and TransplantationAssociation 12:245-55 (1975).

Antacids are used widely, often in large quantities, for indigestion,heartburn or peptic ulcer disease. Despite their consumption in largeamounts and often over long periods of time, phosphorus depletion isuncommon in these settings. This fact is additional evidence of theinefficiency of antacids as phosphorus binding agents.

The inefficiency of commonly used phosphorus binders creates a clinicaldilemma. The dose of the binder must be increased to controlhyperphosphatemia, but increased risk of toxicity of the binder resultsfrom the increased dose. This toxicity includes bone disease andaluminum dementia from aluminum-containing antacids and hypercalcemiaand soft tissue calcification from calcium-containing antacids. Theserisks are particularly problematic in patients with chronic renaldisease.

It would be very useful to have a phosphorus binder available which doesnot have the risks associated with ingestion of presently availablebinders. The binder should be more efficient in binding phosphorus and,thus, would not have to be consumed in the large quantities necessary,for example, when calcium carbonate-containing compositions are used.Such a phosphorus binder would be particularly valuable foradministration to individuals with chronic renal failure, in whomphosphorus retention is a serious concern and the risk of toxicity fromconsumption of presently-available binders is greater than inindividuals in whom kidney function is normal.

U.S. Pat. No. 4,870,105 addresses these concerns by disclosing a calciumacetate phosphorus binder. However, it would be advantageous to find abinder with a smaller anion and, hence, a smaller effective dose.

B. Calcium Formate as a Dietary Supplement

Calcium is an abundant element in the human body and plays an importantrole in many physiological processes. Nutritional and metabolicdeficiencies of calcium can have adverse effects, typically manifestedthrough deficiencies in the structure, function and integrity of theskeletal system. The most common calcium-modulated metabolic bonedisorder is osteoporosis.

A preferred approach to calcium supplementation is through dietarysources. Dairy products are the major contributors of dietary calcium,as are green vegetables (e.g. broccoli, kale, turnip greens, Chinesecabbage), calcium-set tofu, some legumes, canned fish, seeds and nuts.Breads and cereals can contribute significantly to calcium intake.

Calcium supplements may be the preferred way to obtain supplementalcalcium. Calcium carbonate is usually recommended for economic reasons.However, calcium carbonate usage requires sufficient gastric acids forits utilization. Some individuals, especially the elderly, may havelimited amounts of gastric acid, and achlorhydric patients have littlegastric acid. For such cases, calcium carbonate is poorly utilized.Using large amounts of calcium carbonate may also lead to constipationand abdominal distention. Calcium lactate or calcium citrate may then beused.

Needed in the art of calcium supplementation is a very soluble calciumsupplement with smaller anion and, hence, a smaller effective dose.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method of bindingphosphorus in the gastrointestinal tract and, thus, reducing phosphorusabsorption from the intestine. It also relates to a method of reducingserum phosphate levels because phosphorus bound in the gastrointestinaltract results in lower phosphorus absorption than would otherwise occur.It is particularly useful in the treatment and prevention ofhyperphosphatemia in individuals with renal disease or other disease inwhich the ability to excrete phosphorus from the body (e.g., in theurine) is impaired.

The method of the present invention comprises orally administering to anindividual a composition which includes calcium formate in sufficientquantity to effectively bind phosphorus, preferably present in food andbeverages consumed by the individual, and prevent its absorption in theintestine. In an advantageous form of the invention, the calcium formateis administered at a dose of between 0.5 and 10.0 grams.

The present invention is also a method of using calcium formate as adietary calcium supplement. The method comprises orally administratingto an individual a composition comprising calcium formate in sufficientquantities to improve calcium balance or retention.

In an advantageous form of the invention, the calcium formate isadministered in a dose between 0.5 and 3.0 g/day as a supplement.

The present invention is also a pharmaceutical composition comprisingcalcium formate in combination with a pharmaceutically acceptablecarrier. In a preferred embodiment, the composition comprises 0.5 gramsof calcium formate per capsule or tablet. In another preferredembodiment, the composition comprises calcium formate and at least oneadditional therapeutic ingredient. In a most preferred embodiment, thistherapeutic ingredient is a vitamin D compound, typicallycholecalciferol.

It is a feature of the present invention that the amount ofcalcium-containing compound sufficient to inhibit gastrointestinalphosphorus absorption is 10% lighter than therapeutically equivalentamounts of previously known calcium acetate compounds.

It is another feature of the present invention that calcium formate maybe supplied orally to an individual in order to supplement theindividual's calcium intake.

Other objects, features and advantages of the present invention willbecome apparent to one of skill in the art after review of thespecification and claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a calcium formate composition for oraladministration to an individual. The composition is useful in reducingphosphorus absorption in the gastrointestinal tract. Calcium formate isshown below to be effective in inhibiting phosphorus absorption whenadministered orally in in vivo tests and has been shown to prevent theabsorption of ingested phosphorus at a lower dose than othercalcium-containing binders. As a result of these discoveries, calciumformate, alone or in combination with other materials, can be used tobind phosphorus in the gastrointestinal tract, thus reducing thepercentage of an amount of phosphorus consumed (i.e., of a given “dose”of phosphorus) which is absorbed. Preferably, this dose would be0.5-10.0 grams when adjusted to doses intended for human patients.

The present invention also relates to a method of inhibitinggastrointestinal phosphorus absorption. The method of the presentinvention is based on the demonstration that calcium formate is aneffective binder of phosphorus when administered orally to anindividual. The method comprises orally administering a quantity ofcalcium formate sufficient to bind with phosphorus in thegastrointestinal tract. Preferably, this dose is between 10-200milliequivalents of calcium and is preferably present in either tabletor gelatin capsule form. In a most preferable form of the presentinvention, the oral dose is ingested at mealtimes.

As a result of the present invention it is possible to administercalcium formate to reduce absorption of dietary phosphorus, which hasthe net effect of reducing the risks of adverse effects (e.g., bonedisease and secondary hyperparathyroidism) observed in individuals(e.g., chronic renal patients) in whom the ability to excrete phosphorusin the urine is impaired.

As used herein, the term “phosphorus” includes phosphorus and phosphatein its various forms (e.g. HPO₄ ⁻, PO₄ ⁻³, etc.).

According to the method of the present invention, calcium formate isadministered, alone or in combination with other substances (e.g., in ahard gelatin capsule; along with materials necessary to form a tablet orcaplet as a delivery vehicle for the calcium formate; or along with asecond phosphorus binder or other pharmaceutically useful substance) insufficient quantities to reduce phosphorus absorption in thegastrointestinal tract. The calcium formate is administered orally,preferably close in time to food and beverage consumption. By “atmealtimes” we mean within 30 minutes of a meal.

In one embodiment, 0.5-10.0 grams of anhydrous calcium formate (10-200milliequivalents calcium) is taken prior to food consumption (e.g., mealtime) and a second dose of 0.5-10.0 grams of anhydrous calcium formateis taken after food consumption. The dose or quantity to be taken at agiven time varies on an individual-by-individual basis and can beadjusted as needed (e.g., by monitoring serum concentration ofphosphorus and calcium).

In another embodiment of the present invention, calcium formate isadministered, alone or in combination with other substances, insufficient quantities to supplement an individual's calcium intake. TheExamples below indicate that calcium formate in quantities between 0.5and 3.0 g/day are sufficient to improve calcium balance, bone densityand calcium retention.

The present invention is also a pharmaceutical composition comprisingcalcium formate in a pharmaceutically acceptable carrier, wherein thecalcium formate is present in an amount between 0.5-1.0 grams. Inanother embodiment, the pharmaceutical composition comprises calciumformate in amount suitable to inhibit gastrointestinal absorption ofphosphorus, provides between 11 and 44 milliequivalents of calcium, andis 10% lighter than the corresponding calcium acetate dose and is therichest form of calcium available. By “corresponding” or“therapeutically equivalent,” we mean a dose that is equally effective.

In another embodiment of the present invention, the pharmaceuticalcomposition essentially comprises only calcium formate and at least onepharmaceutically carrier, wherein the calcium formate is present in anamount sufficient to produce between 11 and 44 milliequivalents ofcalcium. By “essentially comprises” we mean that calcium formate is theonly active ingredient in the pharmaceutical composition.

The present invention is also a pharmaceutical composition comprisingcalcium formate in a pharmaceutically acceptable carrier combined withother therapeutic agents, preferably a vitamin D compound. Mostpreferably, the calcium formate is combined with vitamin D ischolecalciferol in a range of 125 IU to 400 IU in a tablet or capsule.

EXAMPLE 1 Calcium Formate as a Phosphate Binder in Normal Rats

TABLE 1 Serum (mg %) Serum Ca (mg %) Group % Ca Formate (mean ± SEM)Weight (mean ± SEM) 1 Week on Diet 1 0 4.96 ± .48 209 ± 5.5 ND 2 1 3.25± .31 229 ± 5.5 ND 3 2 2.50 ± .32 211 ± 6.3 ND 4 3  2.5 ± .20 194 ± 6.5ND 2 Weeks on Diet 1 0 5.98 ± .39 295 ± 4.8 11.4 ± .20 2 1 4.70 ± .62211 ± 3.8 14.0 ± .51 3 2  2.7 ± .24 198 ± 5.2 12.8 ± .94 4 3  2.9 ± 0.8150 ± 8.0 12.9 ± 1.3 ND = not determined. There were at least 6 rats pergroup.

Five-week-old Sprague Dawley rats were given a synthetic diet containing0.47% Ca and 0.2% phosphorus for two weeks prior to the addition ofcalcium formate to the diet. Body weights were measured and blood serumwas collected after one or two weeks on calcium formate.

The results of this experiment are tabulated in Table 1. All ratssupplied with calcium formate had less serum phosphorus than controlrats. There seemed to be little difference in serum phosphorus betweenrats on 2% or 3% calcium formate, thus indicating that a saturationbinding point had been reached.

EXAMPLE 2

Twenty 15-day-old weanling rats from Holzmann Company were placed on aan adequate synthetic diet called “Diet 11” (Suda, T., et al., J. Nutr.100:1049-1052, 1970). This diet is supplemented with vitamins A, D, Eand K as described in that paper. Therefore, these are vitaminD-sufficient animals.

The animals were then placed on a basal diet that contains 0.02%calcium, i.e. an extremely low calcium diet. These animals served ascontrols. Another group were placed on the same diet containing calciumformate, providing calcium at 0.25% of the diet. Another group wassupplied calcium formate at 0.47% calcium in the diet, and another groupwas provided 0.47% calcium in the form of calcium carbonate. Growth ofthe animals reflects the ability of the animals to utilize calcium.Using a growth assay of this type to illustrate the effectiveness of thecalcium salt is supported by Steenbock, H. and D. C. Herting, J. Nutr.57:449-468, 1955.

Table 2, below, tabulates the results. Referring to Table 2, we concludethat calcium formate is at least equal to calcium carbonate in abilityto supply calcium to experimental rats. In fact, there is a slightlybetter growth obtain with 0.25% calcium as the formate in comparison toother treatment groups. Calcium formate can therefore be used as adietary supplement to provide dietary calcium.

TABLE 2 Average Body Weight in Grams ± S.E.M for 5 Rats Control DietCalcium Formate Calcium Carbonate Day (0.02% Ca) (0.25% Ca) (0.47% Ca)(0.47% Ca) 7 47.6 ± 10.8 54.3 ± 4.0  51.0 ± 10.6 48.6 ± 4.9  14   74 ±10.7 84.6 ± 5.5  78.0 ± 19   80.4 ± 10.4 21 85.6 ± 10   131.0 ± 5.7* 127 ± 11* 126.2 ± 11*   *Significantly different from control byStudents ‘t’ test. P < 0.001.

1. A method for increasing dietary calcium in a human patient comprisingorally administering to the human a first dose of a first activepharmaceutical ingredient comprising calcium formate in the range of 3.0to 10.0 g wherein the calcium formate is in tablet or in gelatin capsuleform.
 2. The method of claim 1 further comprising orally administering asecond dose of calcium formate in the range of 3.0 to 10 g, wherein thefirst dose is administered before a mealtime and the second dose isadministered after a mealtime.
 3. The method of claim 1, furthercomprising co-administering a second active pharmaceutical ingredient.4. The method of claim 3 wherein the second active pharmaceuticalingredient comprises a vitamin D compound.
 5. The method of claim 4wherein the vitamin D compound comprises cholecalciferol.
 6. The methodof claim 5 comprising cholecalciferol in the range of 125 IU to 400 IU.